Challenge Area and Topic This proposal addresses the broad Challenge Area (15) Translational Science and the specific Challenge Topic 15-DK-106, Translating basic hematology concepts. Abstract Myelodysplastic syndrome (MDS), similar to a number of other hematologic disorders, is associated with a strong anemia and dyserythropoiesis. We have previously identified the NPM1 gene as a strong candidate gene responsible for disease progression in MDS patients with deletion of 5q, the chromosomal region that NPM1 localizes to. In addition, NPM1 plays a key role in ribosome biogenesis. Increasing evidence for ribosomal dysfunction in anemia-associated disorders, including Diamond-Blackfan anemia and dyskeratosis congenita, suggests that aberrant ribosome composition and function may play a role in disease development. By generating models for Npm1 loss in the mouse, we have developed a genetically defined animal model that displays clinical features of MDS, and which has the capacity to develop into myeloproliferative disease (MPD) and acute myeloid leukemia (AML), as is the case for human MDS. Additionally, preliminary data indicate that primary cells from these mice that are haploinsufficient for Npm1 harbor aberrant ribosomes, and such qualitative differences in ribosome composition can lead to significantly different translational expression profiles. Thus we hypothesize that loss of Npm1 can lead to aberrant ribosome formation and qualitative differences in translation that promote disease development. We will address this Challenge using the following specific aims: (1) Characterize functional ribosomes from Npm1 deficient cells;(2) Determine the functional consequences for translation in Npm1 deficient cells;and (3) Validate and confirm Npm1-closs mediated defects in ribosome function in erythropoiesis. PUBLIC HEALTH RELEVANCE: Myelodysplastic syndrome (MDS) and therapy related MDS (t-MDS) are life threatening and incurable disorders. One important aspect of the disease is the presences of anemia. Several lines of evidence implicate ribosomal dysfunction in anemia. NPM, an important ribosome biogenesis gene, is a key player in MDS and a mouse model for Npm1 loss results in an MDS-like disorder. We hypothesize that the phenotype observed is driven in part by aberrant ribosome biogenesis and subsequent defects in translation. We expect that this project will contribute a significant advancement to our understanding of MDS and other hematologic disorders characterized by strong anemia and dyserythropoiesis thereby having a positive impact on human health.